Project summary/Abstract Myelin alterations in neurodegenerative diseases (e.g. multiple sclerosis, MS, or Alzheimer's disease, AD) cause hearing impairments such as sudden hearing loss, inability to localize sound and/or auditory processing disorder. Such deficits are generally attributed to the decrements in conduction velocity and temporal fidelity that accompany axon demyelination. However, the direct impact of myelination alterations on synapse functional parameters, including presynaptic excitability, neurotransmitter release and synaptic plasticity, is largely unknown in the auditory nervous system. To what extent do deficits in synapse function associated with myelination alterations contribute to hearing impairments? The objective of this proposal is to investigate the role of myelination on the functional and structural maturation of the calyx of Held synapse in the auditory pathway. Our published and preliminary studies show that the loss of condensed myelination increases timing errors and failures in synaptic transmission at the calyx synapses in the auditory brainstem. Changes at the level of individual synapses are associated with delayed and degraded signal transmission along the auditory pathway in an in vivo auditory brainstem response test in myelin-deficient rats. Based on the preliminary data, we hypothesize that axon myelination is required for the proper location of ion channels at hemi-nodes and presynaptic terminals, for precision of transmitter release involved in short-term plasticity and for development of a tight synaptic structure. To test this hypothesis, we use the Long-Evans Shaker rat, which completely lacks central myelination, excluding confounding effects associated with inflammatory factors. As a complementary study, we will test whether myelin alterations are a common pathophysiological mechanism of hearing loss observed in AD, we utilize the mouse model of AD, the APP/PS1 mice. In the supplementary study, we will 1) evaluate myelination using immunohistochemistry as well as auditory brain stem response test and 2) assess the synaptic structure with electron microscopy as well as electrophysiology to observe synaptic function in the auditory brainstem of APP/PS1 mice. The results will address the mechanisms of hearing impairment in AD and determine if mouse models of AD show alterations in auditory brainstem function. Our studies on the LES rat are currently underway, and this supplement will allow us to compare whether AD-related pathology and myelin disruption in APP/PS1 mice results in similar impairments. These studies will have a significant impact on our understanding of damaged auditory processing caused by myelin alterations, and contribute to improve treatment of hearing disorders in neurodegenerative diseases (e.g. AD). Furthermore, an improved understanding the consequences of myelin alterations at the synaptic level will have broad relevance for the entire field of neurodegenerative diseases (e.g. MS and AD).